Hyaluronan-cell interactions have been implicated in growth, invasion and metastasis of several types of tumors. However, the manner in which hyaluronan is involved is complex and poorly understood. Perturbation of endogenous hyaluronan-tumor cell interactions by small oligomers of hyaluronan inhibits tumor growth in vivo and reverses several malignant characteristics of tumor cells in vitro. Thus further investigation of these phenomena will lead to increased understanding of the way in which endogenous tumor cell hyaluronan promotes malignancy and the mechanism by which hyaluronan oligomers reverse its effects. The influence of hyaluronan oligomers and of increased endogenous hyaluronan on tumor cell survival and apoptotic pathways will be studied, especially with relation to the phosphatidylinositol-3-kinase/ Akt and Erk pathways. Upstream events that are known to regulate these pathways and that are potential candidates for perturbation by the hyaluronan oligomers are the major focus of the proposed studies. In particular, the influence of these oligomers on the following will be examined: a) ErbB2 activity and interactions of CD44 with ErbB2, ezrin, phosphatidylinositol-3-kinase and cdc37; b) complex formation between cdc37 (a co-chaperone with hsp90) and "nascent" hyaluronan, and its potential role in production, targeting and cellular function of hyaluronan. Finally, the effects of hyaluronan oligomers in vivo on tumor cell apoptosis and growth arrest, tumor angiogenesis, mutagen-induced tumor initiation, and suppression of growth of spontaneous mammary tumors will be assessed. Increased knowledge of the role of hyaluronan in tumor progression and understanding the reversal of its effects by hyaluronan oligomers should lead to innovative therapeutic interventions for human cancer patients. [unreadable] [unreadable]